Application of virtual screening to the discovery of novel nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with potential for the treatment of cancer and axonopathies.

NAMPT may represent a novel target for drug discovery in various therapeutic areas, including oncology and inflammation. Additionally, recent work has suggested that targeting NAMPT has potential in treating axon degeneration. In this work, publicly available X-ray co-crystal structures of NAMPT and the structures of two known NAMPT inhibitors were used as the basis for a structure- and ligand-based virtual screening campaign. From this, two novel series of NAMPT inhibitors were identified, one of which showed a statistically significant protective effect when tested in a cellular model of axon degeneration

Rapid sequence induction: where did the consensus go?

Background Rapid Sequence Induction (RSI) was introduced to minimise the risk of aspiration of gastric contents during emergency tracheal intubation. It consisted of induction with the use of thiopentone and suxamethonium with the application of cricoid pressure. This narrative review describes how traditional RSI has been modified in the UK and elsewhere, aiming to deliver safe and effective emergency anaesthesia outside the operating room environment. Most of the key aspects of traditional RSI – training, technique, drugs and equipment have been challenged and often significantly changed since the procedure was first described. Alterations have been made to improve the safety and quality of the intervention while retaining the principles of rapidly securing a definitive airway and avoiding gastric aspiration. RSI is no longer achieved by an anaesthetist alone and can be delivered safely in a variety of settings, including in the pre-hospital environment. Conclusion The conduct of RSI in current emergency practice is far removed from the original descriptions of the procedure. Despite this, the principles – rapid delivery of a definitive airway and avoiding aspiration, are still highly relevant and the indications for RSI remain relatively unchanged

Bone Mineral Density and Associated Genetic Variants in High-level Caucasian Marathon Runners

INTRODUCTION:Endurance runners (except those who may have low energy availability) tend to have higher total and/or loading site-specific bone mineral density (BMD) in comparison with non-athletes, most likely due to the larger volume of exercise completed. A large genetic component also contributes to BMD, although little is known about which specific genes are involved, whether particular genotypes are sensitive to mechanical loading and the impact of such an interaction on BMD. This study investigated if high-level endurance runners possess enhanced BMD associated with an “advantageous” genetic predisposition, via a potential gene-physical activity interaction.METHODS:Age- and weight-adjusted total BMD (TBMD) and leg BMD (LBMD) measured via Dual-energy X-ray absorptiometry of 67 high-level Caucasian marathon runners (males < 2 h 45 min, n = 37; females < 3 15 min, n = 30) was compared with 40 male and 26 female non-athletes. LRP5 rs3736228, TNFRSF11B rs4355801, VDR rs2228570, WNT16 rs3801387 and AXIN1 rs9921222 variants were then investigated singularly, and collectively, as a total genotype score (TGS) via multivariate analysis of variance in a subgroup of this cohort (male runners n = 19, controls n = 26; female runners n = 17, controls n = 14). RESULTS:Male runners had higher TBMD (1.34 vs 1.28 g/cm2; P=0.02) and LBMD (1.53 vs 1.42 g/cm2; P=<0.01) than non-athletes. Female runners had higher LBMD than non-athletes (1.30 vs 1.22 g/cm2; P=0.02) but not TBMD (1.23 vs 1.18 g/cm2; P=0.22). An interaction (P=0.047) was observed between VDR rs2228570 genotype and group regarding LBMD in males: ff genotype runners had 0.02 g/cm2 higher LBMD than FF or Ff runners, but the FF genotype had the highest LBMD (1.45 g/cm2) amongst non-athletes. LBMD was also 0.12 g/cm2 higher in ff runners compared to ff non-athletes, whereas FF and Ff runners had 0.09 g/cm2 higher LBMD compared to their genotype-matched controls. No other interactions or variants, individually or collectively as part of a TGS, were associated with BMD (P≥0.11). CONCLUSION:High-level female runners possess higher LBMD but not TBMD in comparison with non-athletes whereas male runners possess both higher TBMD and LBMD than non-athletes. Consistent with prior literature, we observed higher BMD in VDR rs2228570 FF genotype in non-athletes, which may be due to increased biological activity associated with the F variant. However, our preliminary data suggest that the ff genotype may be associated with enhanced LBMD in male runners via a gene-environment interaction.Peer reviewedFinal Published versio

Genetic Polymorphisms Related to VO2max Adaptation Are Associated With Elite Rugby Union Status and Competitive Marathon Performance

PURPOSE: Genetic polymorphisms have been associated with the adaptation to training in maximal oxygen uptake (V˙O2max). However, the genotype distribution of selected polymorphisms in athletic cohorts is unknown, with their influence on performance characteristics also undetermined. This study investigated whether the genotype distributions of 3 polymorphisms previously associated with V˙O2max training adaptation are associated with elite athlete status and performance characteristics in runners and rugby athletes, competitors for whom aerobic metabolism is important. METHODS: Genomic DNA was collected from 732 men including 165 long-distance runners, 212 elite rugby union athletes, and 355 nonathletes. Genotype and allele frequencies of PRDM1 rs10499043 C/T, GRIN3A rs1535628 G/A, and KCNH8 rs4973706 T/C were compared between athletes and nonathletes. Personal-best marathon times in runners, as well as in-game performance variables and playing position, of rugby athletes were analyzed according to genotype. RESULTS: Runners with PRDM1 T alleles recorded marathon times ∼3 minutes faster than CC homozygotes (02:27:55 [00:07:32] h vs 02:31:03 [00:08:24] h, P = .023). Rugby athletes had 1.57 times greater odds of possessing the KCNH8 TT genotype than nonathletes (65.5% vs 54.7%, χ2 = 6.494, P = .013). No other associations were identified. CONCLUSIONS: This study is the first to demonstrate that polymorphisms previously associated with V˙O2max training adaptations in nonathletes are also associated with marathon performance (PRDM1) and elite rugby union status (KCNH8). The genotypes and alleles previously associated with superior endurance-training adaptation appear to be advantageous in long-distance running and achieving elite status in rugby union

From inclusion to independence – Training consumers to review research

Health and medical research invariably impacts on the lives of everyday people. Organisations in the developed world are increasingly involving the public in health research projects, and research governance structures and processes. The form the involvement takes varies, as does the level of involvement, from individuals, to groups, to the wider community. Lay community members can be trained to independently review health and medical research, and wider societal involvement in funding decisions, can be effectively fostered. The theoretical foundation, design and development of a task based consumer-training program, including a number of enabling factors to support the success of such training are presented. This work is likely to be of value to those planning to train consumers in technical or complex areas

Association of ACTN3 R577X but not ACE I/D gene variants with elite rugby union player status and playing position

We aimed to quantify the ACE I/D and ACTN3 R577X (rs1815739) genetic variants in elite rugby athletes (rugby union and league), compare genotype frequencies to controls and between playing positions. The rugby athlete cohort consisted of 507 Caucasian men, including 431 rugby union athletes that for some analyses were divided into backs and forwards and into specific positional groups: front five, back row, half backs, centers and back three. Controls were 710 Caucasian men and women. Real-time PCR of genomic DNA was used to determine genotypes using TaqMan probes and groups were compared using Chi-square and odds ratio (OR) statistics. Correction of p-values for multiple comparisons was according to Benjamini-Hochberg. There was no difference in ACE I/D genotype between groups. ACTN3 XX genotype tended to be underrepresented in rugby union backs (15.7%) compared to forwards (24.8%; P=0.06). Interestingly, the 69 back three players (wings and full backs) in rugby union included only six XX genotype individuals (8.7%), with the R allele more common in the back three (68.8%) than controls (58.0%; χ2=6.672, P=0.04; OR=1.60) and forwards (47.5%; χ2=11.768, P=0.01; OR=2.00). Association of ACTN3 R577X with playing position in elite rugby union athletes suggests inherited fatigue resistance is more prevalent in forwards while inherited sprint ability is more prevalent in backs, especially wings and full backs. These results also demonstrate the advantage of focusing genetic studies on a large cohort within a single sport, especially when intra-sport positional differences exist, instead of combining several sports with varied demands and athlete characteristics

Living with severe allergy: an Anaphylaxis Campaign national survey of young people

<p>Abstract</p> <p>Background</p> <p>The transition to adulthood can be particularly challenging for young people with severe allergies, who must learn to balance personal safety with independent living. Information and support for young people and their families are crucial to successfully managing this transition. We sought to: gather insights into the impact of severe allergies on the lives of young people; explore where young people go for information about anaphylaxis and what information they want and need; identify areas where further support is needed.</p> <p>Methods</p> <p>An online questionnaire survey of young people aged 15–25 years with severe allergies in the United Kingdom (UK) was conducted on behalf of the Anaphylaxis Campaign, the main patient support organisation. Participants were recruited mainly from the Anaphylaxis Campaign membership database and also via allergy clinics and social media. The study was funded by the Anaphylaxis Campaign’s In Memoriam Fund.</p> <p>Results</p> <p>A total of 520 young people responded to the survey. The majority had lived with severe allergies since they were young children; 59% reported having attended Accident and Emergency units as a consequence of their allergies. Only 66% of respondents reported always carrying their epinephrine auto-injectors; only 23% had ever used these. Few were currently receiving specialist allergy care; younger respondents were more likely to be under specialist care (34%) than those 18 years and above (23%). Respondents wanted more information about eating out (56%), travelling (54%) and food labelling (43%). Almost a quarter of respondents (23%) reported needing more information on managing their allergies independently without parental help. Managing allergies in the context of social relationships was a concern for 22% of respondents.</p> <p>Conclusions</p> <p>This survey has identified the information and support needs and gaps in service provision for young people with severe allergies. Healthcare professionals and patient support organisations, with the support of the food industry, can help to meet these needs.</p

No association between ACTN3 R577X and ACE I/D polymorphisms and endurance running times in 698 Caucasian athletes

Background: Studies investigating associations between ACTN3 R577X and ACE I/D genotypes and endurance athletic status have been limited by small sample sizes from mixed sport disciplines and lack quantitative measures of performance. Aim: To examine the association between ACTN3 R577X and ACE I/D genotypes and best personal running times in a large homogeneous cohort of endurance runners. Methods: We collected a total of 1064 personal best 1500, 3000, 5000 m and marathon running times of 698 male and female Caucasian endurance athletes from six countries (Australia, Greece, Italy, Poland, Russia and UK). Athletes were genotyped for ACTN3 R577X and ACE ID variants. Results: There was no association between ACTN3 R577X or ACE I/D genotype and running performance at any distance in men or women. Mean (SD) marathon times (in s) were for men: ACTN3 RR 9149 (593), RX 9221 (582), XX 9129 (582) p = 0.94; ACE DD 9182 (665), ID 9214 (549), II 9155 (492) p = 0.85; for women: ACTN3 RR 10796 (818), RX 10667 (695), XX 10675 (553) p = 0.36; ACE DD 10604 (561), ID 10766 (740), II 10771 (708) p = 0.21. Furthermore, there were no associations between these variants and running time for any distance in a sub-analysis of athletes with personal records within 20% of world records. Conclusions: Thus, consistent with most case-control studies, this multi-cohort quantitative analysis demonstrates it is unlikely that ACTN3 XX genotype provides an advantage in competitive endurance running performance. For ACE II genotype, some prior studies show an association but others do not. Our data indicate it is also unlikely that ACE II genotype provides an advantage in endurance running